The goals of this study are to use molecular biological techniques to identify and characterize the genetic aberrations in both preneoplastic lesions and tumors of epithelial origin, and to explore the potential use of these specific genetic lesions as markers for the early detection of cancer. Molecular alterations such as activation of oncogenes and loss of tumor suppressor genes have been shown to be important in early stages of the pathogenesis of many human neoplasms. We have chosen to study colorectal and endometrial cancers in which activating mutations of the ras oncogene and deletion or mutation of the tumor suppressor gene p53 are frequently present. Currently we are studying specimens obtained from 15 colorectal cancer patients accrued on a multicenter case control study carried out at the National Naval Medical Center, Bethesda, Maryland. Paired specimens obtained from each patient include a surgically excised colonic adenocarcinoma and preoperatively obtained and lyophilized stool specimens which contain shed epithelial cells. These specimens will be analyzed by PCR amplification, RFLP analysis, and sequencing for activated Ki-ras and p53 mutations. Molecular analysis will also be performed on control subjects to assess the specificity of these tests. Subsequent statistical analysis will be done to identify the power of association between an identified abnormality in the DNA recovered from the primary tissue and stool samples. We are also interested in identifying the molecular changes occurring in both premalignant lesions of the endometrium and endometrial cancers, and are presently characterizing the presence of Ki-ras and p53 gene mutations in a group of endometrial curettage specimens spanning the histologic spectrum from benign to malignant. Our preliminary data show the presence of Ki-ras mutations in 6% of proliferative endometrium, 5% of simple hyperplasias, 14% of atypical hyperplasias, and 9% of carcinoma samples. Mutations in the p53 gene were found in 6%, 5%, 7%, and 13% of proliferative endometrium, simple hyperplasia, atypical hyperplasia, and endometrial carcinoma specimens respectively. These results indicate that not only are these mutations likely to be initiating events in the oncogenesis of endometrial cancers, but that it is possible to detect these mutations in DNA extracted from small amounts of tissue to accurately assess the presence of early events in the development of neoplasms. We plan to look for other molecular aberrations which occur early in oncogenesis, might be present with higher frequency in endometrial lesions, and thus could be reasonably applied toward development of screening tests. Furthermore, molecular analyses such as those described above will also be applied to other epithelial tumors with the intent of developing new screening modalities for the early detection of common epithelial malignancies.